Stress is any actual or perceived disturbance of an organism’s environment. The
acute response to stress includes the release of corticotropin-releasing factor (CRF) from
the hypothalamus to activate the pituitary and downstream glucocorticoid secretion. In
addition to this classical role, CRF also influences many extra-hypothalamic brain
regions including the striatum and the hippocampus. CRF and the related stress peptide
Urocortin 1 (UCN) exert their cellular effects by binding to one of two cognate G-protein
coupled receptors (GPCRs), CRF receptor 1 (CRFR1) or 2 (CRFR2). While these GPCRs
were initially characterized as being coupled to adenylyl cyclase, cAMP and PKA
signaling, it has since become clear that CRFRs couple to numerous intracellular
signaling cascades. Here, I describe work elucidating the intracellular signaling pathways
by which stress peptides influence both striatal and hippocampal neurons. This document
describes a novel intracellular signaling pathway whereby CRF and UCN lead to a rapid
Gβγ-dependent increase in phosphorylation of the activity-dependent transcription factor
CREB. These data not only describe a completely original mechanism of stress peptide
signaling in neurons, but also include the first direct demonstrations of Gβγ-mediated
CREB phosphorylation in any cellular system. Together, these results suggest that stress
peptide influence of Gβγ signaling may be a fundamental, yet underexplored, molecular
mechanism by which stress influences both the central nervous system and other stresspeptide
University of Minnesota Ph.D. dissertation. December 2010. Major: Neuroscience. Advisor: Paul Gary Mermelstein, Ph.D. 1 computer file (PDF): vii, 77 pages. Ill. (some col.)
Stern, Christopher Michael.
A novel molecular mechanism of stress peptide action in neurons..
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